Oncogene (2000) 19, 2557 ± 2565
ã 2000 Macmillan Publishers Ltd All rights reserved 0950 ± 9232/00 $15.00
www.nature.com/onc
Jak-Stat signal transduction pathway through the eyes of cytokine class II
receptor complexes
Sergei V Kotenko1 and Sidney Pestka*,1,2
1
Department of Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson
Medical School, Piscataway, New Jersey, NJ 08854-5635, USA; 2Cancer Institute of New Jersey, 195 Little Albany Street, New
Brunswick, New Jersey, NJ 08901, USA
Cells of the immune system communicate with each other
to initiate, establish and maintain immune responses. The
communication occurs through cell-to-cell contact or
through a variety of intercellular mediators that include
cytokines, chemokines, growth factors and hormones. In
the case of cytokines, the signal is transmitted from the
outside to the inside of a cell through cell surface
receptors speci®c for each cytokine. At this step the
signal is also decoded and ampli®ed: ligand binding
causes recruitment and/or activation of numerous
cytoplasmic proteins. One cytokine can activate a
number of signal transduction pathways leading to
regulation of a wide array of biological activities. One
of these pathways, the Jak-Stat pathway, is brie¯y
reviewed here with respect to the class II cytokine
receptors. Signal transduction through receptors for
interferons Type I (IFN-a, IFN-b, IFN-o) and Type II
(IFN-g), and interleukin 10 (IL-10) is described in detail.
In addition, a complex between tissue factor (TF) and
coagulation factor VIIa, and two new receptors related
to the class II cytokine receptor family are discussed.
Oncogene (2000) 19, 2557 ± 2565.
Keywords: cytokines; interleukin-10; interferons; receptors; IFN-8; IFN-a
The Jak-Stat signal transduction pathway is activated by
many polypeptide ligands. The initial event leading to
the signaling cascade is the binding of a ligand to its
speci®c cell surface receptor. Two cytokine receptor
families, class I and class II, are primarily utilized by
ligands inducing the Jak-Stat pathway. These two
families are characterized by their patterns of conserved
amino acid residues within the receptor extracellular
domains (Bazan, 1990; Thoreau et al., 1991). The class I
family has numerous members; cytokines utilizing these
receptors activate a number of signal transduction
pathways beside the Jak-Stat pathway. Whereas there
are fewer class II family members, they are more speci®c
in their choice of signal transduction pathways: so far,
they tend to prefer Jak-Stat signaling over other
pathways. Cytokine signaling through class II receptor
complexes (Figure 1) is the subject of this review.
Speci®cally, receptor complexes for type I and type II
interferons (IFNs) and interleukin-10 (IL-10) and their
ligand-induced signal transduction events will be brie¯y
reviewed in this article. In addition, a distinct complex
*Correspondence: S Pestka, Cancer Institute of New Jersey, 195
Little Albany Street, New Brunswick, New Jersey, NJ 08901, USA
between coagulation factor VIIa (FVIIa) and tissue
factor (TF), which belongs to the class II cytokine
receptor family and may mediate signaling, will also be
discussed. Other aspects of these receptors have also been
recently reviewed (Domanski and Colamonici, 1996;
Kirchhofer and Nemerson, 1996; Pestka et al., 1997a;
Carmeliet and Collen, 1998; Mogensen et al., 1999).
The class II cytokine receptor family consists of
seven members with known function: tissue factor,
three pairs of two receptor subunits of the receptor
complexes for either type I (IFN-a, IFN-b, IFN-o, and
IFN-t) and type II (IFN-g) IFNs and IL-10. In
addition, there are currently two orphan receptors
CRF2-8 and CRF2-9 (Kotenko and Pestka, unpublished data; Lok et al., 1999a,b). The extracellular
domains of the class II receptors have tandem
®bronectin type III (FNIII) domains. Most known
family members have two tandem FNIII domains,
although a subunit of the type I IFN receptor complex
(IFN-aR1) has four tandem domains (Figure 2). The
structures of the soluble extracellular domains of tissue
factor and one subunit of the type II IFN receptor
complex (IFN-gR1) have been determined (Harlos et
al., 1994; Walter et al., 1995; Banner et al., 1996). Their
intracellular domains vary in length and do not
demonstrate any similarity in their primary structures.
Four receptor chains, IFN-aR1, IFN-aR2, IL-10R2
and IFN-gR2 are clustered on human chromosome 21
(Jung et al., 1987; Lutfalla et al., 1990, 1993, 1995;
Langer et al., 1990; Soh et al., 1993,1994a,1994b;
Reboul et al., 1999). IFN-aRI has also been designated
the a-chain (IFN-aRa) comparable to other cytokine
receptor chains that bind ligand. It should be noted
that for many receptor complexes, two or more chains
can contribute to ligand-binding so that naming a ®rst
ligand-binding component the a-chain may be fraught
with erroneous implications. Furthermore, because the
genetic nomenclature for human and mouse genes does
not permit use of Greek letters, the designation of
components with Greek letters immediately requires
that the gene be designated by a di€erent abbreviation
than the protein. Thus, the recommended numerical
nomenclature was derived with these notions in mind
and provides abbreviations where the genes and the
proteins use the same alliteration. For additional
details of nomenclature see (Pestka et al., 1997a).
Two receptor chains, IFN-gR1 and CRF2-8, map to
Chr. 6 (Rashidbaigi et al., 1986; Lok et al., 1999a), two
chains, TF and CRF2-9, are encoded on Chr. 1
(Carson et al., 1985; Lok et al., 1999b) and the IL10R1 chain is encoded on Chr. 11 (Taniyama et al.,
1995). Members of the Jak family of tyrosine kinases
associated with these receptors have been identi®ed in a
Cytokine class II receptors
SV Kotenko and S Pestka
2558
reviews Pestka et al., 1987, Pestka, 1997b; Moore et al.,
1993).
Both IFN-g and IL-10 are homodimers and their
crystal structures have been reported (Ealick et al.,
1991; Walter and Nagabhushan, 1995; Zdanov et al.,
1995). They have signi®cant homology in their tertiary
structures despite the lack of signi®cant homology
between their primary structures. Thus, it was not
surprising that, when the receptor chains for these
ligands were identi®ed, the structure of the functional
IFN-g and IL-10 appeared to be similar although they
utilize distinct receptor subunits for signaling (Figures
3 and 4) and subsequently activate distinct but
overlapping combinations of Jak and Stat proteins.
Although the crystal structure of only one ligandreceptor complex of this family of receptors, IFN-g and
soluble IFN-gR1, has been reported (Walter et al.,
number of studies and information about Stat
recruitment sites is also summarized (Figure 1 and
Table 1). The orphan receptor chains (CRF2-8 and
CRF2-9) possess classical Stat3 recruitment sites
(YXXQ) and likely a Jak1 association site (Stahl et
al., 1995; Usacheva et al., 2000).
Ligands utilizing class II cytokine receptors for
signaling, namely IFNs and IL-10, are important
immunomodulators able to induce a broad variety of
biological responses depending on the cell type and
speci®c conditions and/or additional costimulators.
Type I IFNs, which include the family of IFN-as,
IFN-b, and IFN-o, are initial vital signals for cells and
the immune system to initiate an antiviral response.
IFN-g and IL-10 are primarily involved in regulation
of speci®c immune responses, promoting (driving
toward) TH1 or TH2-like responses, respectively (see
Figure 1 Class II cytokine receptor family. IL-10R1 and IL-10R2 are two subunits of the IL-10 receptor complexes (Lutfalla et al.,
1993; Liu et al., 1994; Kotenko et al., 1997). IFN-gR1 and IFN-gR2 are two subunits of the IFN-g receptor complex (Aguet et al.,
1988; Soh et al., 1994a). IFN-aR1 and IFN-aR2 are two subunits of the type I IFN receptor complex; IFN-aR2 has two membrane
bound splice variants, IFN-aR2c with longer intracellular domain and IFN-aR2b with shorter intracellular domain (Uze et al.,
1990; Novick et al., 1994; Domanski et al., 1995; Lutfalla et al., 1995). Only IFN-aR2c (IFN-aR2 shown in the Figure) is thought to
be competent for Jak and Stat recruitment and signaling. Tissue factor (TF) is a receptor for coagulation factor VIIa (FVIIa)
(Scarpati et al., 1987; Fisher et al., 1987; Spicer et al., 1987; Morrissey et al., 1987). Orphan receptors CRF2-8 and CRF2-9 are also
diagramed and the `?' means the ligand for them has not been identi®ed (Kotenko and Pestka, unpublished data; Lok et al.,
1999a,b). Jak members associated with the intracellular domains of the receptors and Stat members recruited directly or indirectly
(in parentheses) through these receptors are shown. The dashes indicate these receptors do not recruit Stats or associated with Jaks.
The `3?' and `Jak1?' means we predict that Stat3 and Jak1, respectively, recruited to the receptor chain based on the structure of the
intracellular domain. Chromosomal locations of the receptors are also shown. The number of amino acid residues comprising the
extracellular (signal peptide), transmembrane and intracellular domains of the receptors is shown for each of the receptor chains
Table 1 Class II cytokine receptors
Ligand
Receptor chains
Chromosomal location
Stats
Jaks
IFN-a
IFN-aR1
21
±
Tyk2
IFN-aR2
21
1, 2, 3
Jak1
IFN-g
IFN-gR1
6
1, (3)
Jak1
IFN-gR2
21
±
Jak2
IL-10
IL-10R1
11
3, (1)
Jak1
IL-10R2
21
±
Tyk2
FVIIa
?
TF
1
±
±
CRF2-8
6
3?
Jak1?
?
CRF2-9
1
3?
Jak1?
Receptor chains are as indicated in the legend for Figure 1. Chromosomal locations of human receptor chains are shown. Jak members
associated with the intracellular domains of the receptors and Stat members recruited directly or indirectly (in parentheses) through these
receptors are shown. The dashes indicate the intracellular domains of these chains do not recruit Stats and/or Jaks, as noted in the Table. The `?'
means the ligand has not been identi®ed; and `3?' and `Jak1?' means we predict that Stat3 and Jak1, respectively, recruited to the receptor chain
based on the structure of the intracellular domain
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SV Kotenko and S Pestka
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Figure 2 Alignment of amino acid sequences of the extracellular domains of class II cytokine receptors. Full length extracellular
domains with signal peptides are shown for both chains of the IFN-g and IL-10 receptor complexes, IFN-gR1 and IFN-gR2, and
IL-10R1 and IL-10R2, respectively, for the second chain of the IFN-a receptor complex, IFN-aR2, for TF and for two orphan
receptors, CRF2-8 and CRF2-9. The extracellular domain of the IFN-aR1 chain is divided into two segments: signal peptide and Nterminal D200 domain comprise IFN-aRln and the C-terminal D200 is designated here IFN-aR1c
1995), the common architecture of the IL-10 and IFNg receptor complexes suggests that IL-10 and IFN-g
signaling involve the same basic events (Figures 3 and
4). Both ligands are homodimers which bind to two
molecules of their respective ligand binding receptor
chains (the IFN-gR1 or IL-10R1 chains or R1; also
designated Ra chains) which also serve as the signal
transducing (Stat recruiting) receptor chains. But these
events alone are not sucient for signaling. The model
(Figures 3 and 4) illustrates that the binding of the
ligand homodimers to the R1 chains results in
formation of a non-functional intracellular receptor
complex as previously demonstrated (Rashidbaigi et
al., 1986; Jung et al., 1987, 1988, 1990). The second
chains (the IFN-gR2 or IL-10R2 chains, or R2 chains;
also designated Rb chains) are required to assemble an
active intracellular receptor complex and thus to
initiate the signal transduction events (Figures 3 and
4) (Kotenko et al., 1995, 1996, 1997, 1999). The
intracellular domains of both the IFN-g and IL-10 R1
chains are associated with Jak1, whereas the second
chains bring to their respective complexes distinct Jak
family members associated with the R2 intracellular
domains. The IFN-gR2 chain associates with Jak2 and
the IL-10R2, with Tyk2. Ligand-induced oligomerization of receptor components results in Jak activation
leading to phosphorylation of the R1 intracellular
domains on Tyr residues. The functions of di€erent
Jaks in the various receptor complexes are not
equivalent. For example, the Jak1 negative U4A cells
expressing a kinase negative Jak1 mutant exhibit some
activities in response to IFN-g, indicating that Jak1
predominantly plays a structural role in the IFN-g
receptor complex rather than a catalytic role. In
contrast, the Jak2 negative g2A cells expressing a
kinase negative Jak2 mutant do not respond to IFN-g
(Briscoe et al., 1996). After the phosphorylation of the
R1 intracellular domains occurs, Stats are then
recruited to the receptor complexes based on speci®c
interaction of Stat SH2 domains with appropriate
phosphotyrosine motifs within the R1 intracellular
domains. The R2 intracellular domains do not possess
Stat recruitment or docking sites and thus do not
participate in the Stat recruitment process. The Stats
are then phosphorylated on Tyr residues resulting in
homo- or heterodimer formation, dissociation from
receptors and nuclear translocation. In the nucleus the
Stat dimers bind to speci®c regions of promoters of
cytokine-responsive genes and participate with other
transcriptional factors, enhanceosomal and transcriptosomal proteins and other factors (Schaefer et al.,
1995; Halle and Meisterernst, 1996; Bhattacharya et
al., 1996; Zhang et al., 1996; Horvai et al., 1997; Carey,
1999; Gall et al., 1999; Pollack et al., 1999; Paulson et
al., 1999; Nakashima et al., 1999; Zhang et al., 1999).
These complexes then modulate the ®nely-tuned and
well-orchestrated transcription of cytokine-regulatable
genes.
The combinations of Stats activated by IFN-g and
IL-10 are distinct and in some aspects opposing. IFN-g
triggers Stat1 and, in some cases, dependent on the cell
type, speci®c conditions and/or ratio of receptor
subunits expressed, a small amount of Stat3 (Shuai et
al., 1992; Horvath et al., 1995; Sato et al., 1997;
Caldenhoven et al., 1999; Kotenko et al., 1999). In
contrast, Stat3 and a small amount of Stat1 are
activated during IL-10 signaling (Finbloom and Winestock, 1995; Wehinger et al., 1996; Kotenko et al.,
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SV Kotenko and S Pestka
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Figure 3 Model of the cytokine class II receptor complexes and signal transduction. A and B. IFN-g (a) or IL-10 (b) homodimers
bind to their ligand binding R1 chains. The corresponding second chains (helper or accessory receptors IFN-gR2 or IL-10R2,
Kotenko et al., 1996, 1997, 1999) are then recruited to the complexes to initiate signal transduction events in the Jak-Stat pathway.
Stats are recruited through the ligand binding chains (signal transducing receptors, Kotenko et al., 1996). IFN-a (c) binding to the
subunits of the type I IFN receptor complex, the IFN-aR2c and the IFN-aR1 chains, initiates the cascade of signal transduction
events. All Stats involved in IFN-a signaling are activated through the intracellular domain of the IFN-aR2c chain (Kotenko et al.,
1999). Signal transduction events activated upon binding of FVIIa (d) to TF are not well de®ned
Figure 4 Model of the IFN-g and Epo receptor complexes. (a) represents the active heteromeric IFN-g receptor complex with two
IFN-gR1 and two IFN-gR2 subunits per complex. The IFN-g homodimer binds to two IFN-gR1 chains, followed by its interaction
with two IFN-gR2 chains. The association with receptor subunits Jak1 and Jak2 kinases (or other members of the Jak family
substituting for Jak2) activate one another by transphosphorylation initiating the signaling cascade. JAS, represents Jak association
site; SRS, Stat recruitment site; ST, signal transducing receptor; AC, accessory chain receptor; PTK, protein tyrosine kinase; gR2/X,
chimeric receptor with the extracellular domain of the IFN-gR2 and the intracellular domains of various receptors swapped for the
intracellular domain of the Hu-IFN-gR2 chain (Kotenko et al., 1996). (b) represents the IFN-gR1 homodimer bound to IFN-g. The
cytoplasmic domains of the two chains are too far apart to permit transactivation of the two Jak1 kinases. (c) depicts the EpoR/gR1
homodimer which, unlike the IFN-gR1 homodimer, permits transactivation of the two Jak1 molecules
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Cytokine class II receptors
SV Kotenko and S Pestka
1997). A single phosphotyrosine motif (YDKPH)
within the IFN-gR1 chain is responsible for Stat1
recruitment (Greenlund et al., 1994). Stat3 can be
recruited to the tyrosine-phosphorylated IL-10R1
intracellular domain through the interaction with two
Stat3 docking sites (Weber-Nordt et al., 1996).
Mechanisms of Stat3 activation by IFN-g as well as
Stat1 activation by IL-10 have not been delineated.
One possibility is that Stat1 or Stat3 can be activated
in cells through activated Stat3 or Stat1, respectively;
alternatively, the detection of the small amount of
activated Stat1 by IL-10 or Stat3 by IFN-g does not
occur in cells and might be an artifact of the EMSA.
In this context it is interesting to note that IFN-g
and IL-10 act antagonistically, particularly in the
regulation of TH1 and TH2 dependent immune
responses; in addition, macrophage activation by
IFN-g is inhibited by IL-10 (Moore et al., 1993). A
number of mechanisms regulating this crosstalk can be
proposed. It is possible that both cytokines use a
similar approach to control T cells: the di€erential
expression of the IL-10 or IFN-g receptor second
chains in T cell subsets, as already shown in the case of
the IFN-gR2 chain (Pernis et al., 1995; Bach et al.,
1995; Sakatsume and Finbloom, 1996; Novelli et al.,
1996; Skrenta et al., 1996). Alternatively, since Jak1 is
activated by both ligands, if one of the R1 chains has a
higher anity site for Jak1 binding than the other R1
chain, and if the amount of Jak1 is limited in a cell,
then the two receptor complexes may compete for Jak1
recruitment required for a functional receptor complex.
Another possible mechanism may occur at the level of
Stat activation. The heterodimeric Stat1:Stat3 complex
may have a higher association constant than the
Stat1:Stat1 homodimeric complex. In this scenario
Stat3 will sequester activated Stat1 and prevent
formation of Stat1 homodimers. Thus, only when the
level of activated Stat1 exceeds the level of activated
Stat3, are Stat1 homodimers formed and able to
initiate speci®c biological e€ects.
It is also likely that a minimal level of Stat1
activation is required to induce biological e€ects. This
may explain our previous observations that, despite the
fact that a small amount of Stat1 is activated by IL-10
or by modi®ed IFN-g receptor chains where the Stat1
recruitment site is substituted by a Stat3 recruitment
site, the activation of Stat1 did not lead to activation
of IFN-g speci®c biological activities (Kotenko et al.,
1997, 1999).
Less is known about the structure of the IFN-a/b/o
receptor complex. It is not certain whether type I IFNs
interact with their receptor complex as monomers,
dimers or trimers. It is likely that IFN-a interacts with
the receptor as a monomer and IFN-b as a monomer
or dimer (Pestka et al., 1983; Kempner and Pestka,
1986; Arduini et al., 1999). Two subunits of the type I
IFN receptor complex were identi®ed: Hu-IFN-aR1
and Hu-IFN-aR2 and its variants (Figures 1 and 3).
The major ligand binding chain is the Hu-IFN-aR2
chain (Novick et al., 1994; Domanski et al., 1995;
Lutfalla et al., 1995; Cutrone and Langer, 1997). This
receptor chain is expressed as three variants resulting
from di€erential mRNA splicing. One, the Hu-IFNaR2a chain, is secreted, and the other two are
membrane bound proteins with di€erent lengths of
their cytoplasmic domains: the IFN-aR2b chain with a
shorter cytoplasmic domain than the IFN-aR2c chain.
All these variant forms have the same extracellular
domain and bind the ligands. However, only the IFNaR2c chain, which has the longer cytoplasmic domain,
seems to function in signaling. The IFN-aR1 chain
exhibits a distinct structural feature not present in
other members of cytokine receptor class II family: its
extracellular domain is twice the size of the extracellular domains of other members of this family,
having four tandem FNIII domains rather than two.
The IFN-aR1 chain binds most type I IFNs weakly at
best, but modulates the di€erential recognition of type
I IFNs by the IFN-aR2/IFN-aR1 complex (Cutrone
and Langer, 1997). A soluble complex of human IFN-b
with the extracellular domains of the IFN-aR1 and
IFN-aR2 chains has an apparent stoichiometry of
1 : 1 : 1 (Arduini et al., 1999). All type I IFNs activate
Jak1 and Tyk2 tyrosine kinases during signal transduction leading to formation and activation of ISGF3
(IFN-a-Stimulated Gene Factor 3) DNA-binding
complexes consisting of Stat1 and Stat2 transcriptional
factors and p48 DNA-binding protein from the IFN
regulatory factor (IRF) family of proteins (Fu et al.,
1990, 1992; Schindler et al., 1992; Veals et al., 1992;
Velazquez et al., 1992; MuÈller et al., 1993). Jak1 is
associated with the IFN-aR2c intracellular domain
whereas the IFN-aR1 intracellular domain is associated
with Tyk2 (Colamonici et al., 1994; Domanski et al.,
1997). Type I IFNs activate Stat1, Stat2 and Stat3
through the IFN-aR2c intracellular domain (Kotenko
et al., 1999; Nadeau et al., 1999). The IFN-aR1
intracellular domain does not recruit Stats, but
supports type I IFN signal transduction by bringing
Tyk2 tyrosine kinase to the receptor complex. However, the IFN-aR1 intracellular domain can modulate
type I IFN signaling: the deletion of amino acids 525 ±
544 of the IFN-aR1 intracellular domain created a
receptor which produced an enhanced response (Gibbs
et al., 1996).
These three receptor complexes de®ne a paradigm of
signaling for cytokines utilizing class II cytokine
receptors (Pestka et al., 1997a). Ligand binding induces
oligomerization of receptor subunits (Figures 3 and 4).
The receptor chains can be divided into two classes: (1)
the actual Signal Transducers (ST), containing Stat (or
other SH2 domain containing protein) Recruitment
Sites (SRS) and Jak Association Sites (JAS); and (2)
Accessory Chain (AC), containing only JAS, but no
SRS. The higher anity ligand binding chains of the
receptor complexes of the class II cytokine receptor
family (IFN-gR1, IL-10R1 and IFN-aR2) are associated with Jak1 and, in addition, serve as the Stat
recruitment chains. The primary function of the second
chains of these receptors is to bring an additional
tyrosine kinase to the receptor complexes, causing Jak
cross-activation and initiation of signal transduction
(Kotenko et al., 1995, 1996, 1997, 1999; Bach et al.,
1996). The second chains do not recruit Stats. The
intracellular domains of the AC can be swapped with
the intracellular domains of other receptors. These
substitutions bring other Jaks to the receptor complexes without a€ecting signaling. Thus, the particular
Jak kinase recruited to the AC does not provide
speci®city for signal transduction (Figure 4). Only their
extracellular domains are speci®c for particular ligand
receptor complexes. The Jaks show preferential
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SV Kotenko and S Pestka
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speci®city for association with the receptor intracellular
domains, but the kinases per se are promiscuous and
interchangeable for the Jak-Stat signal transduction
pathway (Kotenko et al., 1996, 1997).
Within the cytokine class I receptor family there are
cases where homodimerization of a single receptor
chain appears sucient for signal transduction. In
these instances, the receptor intracellular domain
contains all the JAS and SRS regions necessary and
sucient for signal transduction (as in the case of
EpoR, GHR or ProR2), the activation of a single Jak2
is observed and a separate accessory chain is not
required (Argetsinger et al., 1993; Witthuhn et al.,
1993; Campbell et al., 1994; DaSilva et al., 1994; David
et al., 1994; Dusanter-Fourt et al., 1994; Rui et al.,
1994). However, the Epo-induced homodimerization of
a chimeric protein with the EpoR extracellular domain
and the IFN-gR1 intracellular domain (EpoR/gR1) was
sucient for induction of IFN-g-like signaling (Figure
4) (Muthukumaran et al., 1997). In contrast, the
ligand-induced homodimerization of appropriate R1
subunits of the native IFN-g and IL-10 receptor
complexes without subsequent recruitment of R2
subunits does not cause initiation of a signal transduction cascade (Figure 4). The explanation appears to
come from the geometry of the receptor complexes.
When the crystal structure of the IFN-g:IFN-gR1
complex was solved (Walter et al., 1995) it became
clear that, when one IFN-g homodimer binds two IFNgR1 molecules, the two receptor subunits do not
interact with one another and are separated by 27AÊ
(Walter et al., 1995) at their closest point. Therefore,
though the IFN-gR1 chain possesses both a Jak1
association site and a Stat1a-recruitment site, alone it is
unable to transduce a signal on homodimerization as
the two Jak1 kinases are not in physical proximity to
permit transphosphorylation. In contrast, GH- or Epoinduced homodimerization of the GHR (de Vos et al.,
1992) or the EpoR (Watowich et al., 1992) brings the
intracellular domains of these receptors into close
proximity allowing interaction of receptor-associated
Jak2 molecules. Therefore, in the chimeric EpoR/gR1
dimer, two Jak1 kinases are brought suciently close
together to activate one another, albeit ineciently
(Figure 4) (Muthukumaran et al., 1997).
Thus the cytokine class II receptor complexes
possess a unique characteristic feature of the receptors
relative to the positioning of the Jaks. The geometry of
the receptor complexes is such that homodimerization
of their R1 chains yields a non-functional intracellular
receptor complex. The accessory R2 chain completes
this function. We speculate that the presence of two
distinct chains provides for more e€ective control and
®ne tuning of responses to ligand, and permits
interactions with additional cellular components and,
possibly, multiple pathways.
However, it seems likely that at least one member of
the cytokine class II receptor superfamily does not
follow the paradigm. Tissue factor, while a member of
the class II cytokine receptor family, stands far apart
from the receptor complexes for IFNs and IL-10. The
crystal structure of the FVIIa:TF complex has been
solved and is very di€erent from that of the IFNg:IFN-gR1 complex (Walter et al., 1995; Banner et al.,
1996). First, the residues within the TF extracellular
domain interacting with the FVIIa are distinct from
residues within the IFN-gR1 involved in interaction
with IFN-g. Second, its ligand, the coagulation factor
FVII, is a serine/threonine protease, a very unusual
ligand for cytokine receptors. It does not demonstrate
any structural similarity to either the IFNs or IL-10.
Nevertheless, recent reports implicate induction of
certain biological activities in cells after binding of
FVIIa to TF, suggesting the existence of signal
transduction events (Bromberg et al., 1995; Pendurthi
et al., 1997; Ollivier et al., 1998; Poulsen et al., 1998;
Cunningham et al., 1999; Camerer et al., 1999). While,
there is no data demonstrating direct activation of the
Jak-Stat pathway by TF:FVIIa complex, cells transfected with a reporter gene under control of the IFN-ginducible promoter responded to FVIIa treatment by
upregulation of reporter gene expression, although the
authors suggested that MAP kinase activation was
responsible for FVIIa-induced transcription of a
reporter gene (Figure 3) (Poulsen et al., 1998). It is
not clear how this unusual couple TF:FVIIa evolved so
far from the more classical cytokine class II ligand :
receptor complexes. It is possible that TF plays role of
the accessory chain, like R2 for the IL-10 or IFN-g
receptor complexes or IFN-aR1 for the IFN-a receptor
complex, but acquired the ability to bind its ligand
FVIIa with high anity. However, the experiments
with chimeric receptors do not demonstrate the ability
of the TF intracellular domain to associate with Jaks
(Kotenko and Pestka, unpublished data). It remains to
be seen whether the TF intracellular domain is
responsible for initiation of signaling or whether there
is an another yet unidenti®ed receptor subunit for
FVIIa which transduces the signal alone or with the
support of the TF intracellular domain. Two orphan
class II receptors are possible candidates for an
FVIIaR2 chain.
When studied in greater detail, the Jak-Stat pathway,
originally discovered as a seemingly simple straightforward pathway (ligand:receptor pair ? Jaks ? distinct
set of Stats ? speci®c biological e€ects), seems more
and more complex with cross talk with other pathways.
Numerous divergent interacting partners of Jaks and
Stats have been discovered revealing or just suggesting
many new, unpredictable functions for Jaks and Stats
(KlingmuÈller et al., 1995; Marrero et al., 1995;
Yamauchi et al., 1997; Guillet-Deniau et al., 1997;
Pollack et al., 1999, 2000). The Jak-Stat signal
transduction pathway has evolved, likely together with
cytokine families, from such lower eukaryotes as
Dictyostelium discoideum (Adler et al., 1996; Kawata
et al., 1997; Araki et al., 1998). Along the evolutionary
path, it acquired many new alternative functions but
also retained at least partially, some original ancestral
functions. Evolution from common ancestors may
explain the fact that many cytokines activate an array
of overlapping functions (Fambrough et al., 1999). The
speci®city of cytokine signaling developed during the
expansion of the pathway has only started to be
revealed. In spite of numerous elegant studies spotlighting certain aspects and mechanisms of the pathway, it seems likely that the Jak-Stat signaling network
is still far from being completely elucidated.
Many directions remain to be explored in the area of
cytokine class II receptors and signaling. Identi®cation
of new receptors and their ligand partners (Kotenko
and Pestka, unpublished data; Kotenko et al., 2000)
Cytokine class II receptors
SV Kotenko and S Pestka
and at least one unusual receptor:ligand pair (TF,
FVIIa) requires a new perspective and, perhaps, some
additional missing elements. The solution of the
structure of several ligand:receptor signaling complexes
should help to extend the existing paradigm for
cytokine class II receptor complexes and signaling.
Abbreviations
EpoR, Erythropoietin receptor; GHR, growth hormone
receptor; ProR, prolactin receptor.
Acknowledgments
We thank Eleanor Kells for assistance in the preparation of
the manuscript and Jerome Langer and Michael Newlon for
the critical review of the text. This study was supported in
part by American Heart Association Grant
AHA#9730247N and by State of New Jersey Commission
on Cancer Research Grant#799-021 to SV Kotenko, and
by United States Public Health Services Grants RO1CA46465 and 1P30-CA72720 from the National Cancer
Institute, RO1 AI36450 and RO1 AI43369 from the
National Institute of Allergy and Infectious Diseases and
an award from the Milstein Family Foundation to S Pestka.
2563
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